Cancer stem cells (CSCs)/tumor-initiating cells have been defined as a subset of tumor cells responsible for initiating and sustaining tumor development. It was evidenced that the existence of lung CSCs and their stem cell properties contributed to the tumorigenesis and drug resistance. (Hanahan D and Weinberg R A.; Hallmarks of cancer: the next generation. Cell, 144:646-74, 2011.) It was also well known that to regulate carcinogenesis of lung cancer facilitated the search of novel therapeutics which specifically targeted lung cancer stem cells (LCSCs) and/or CSCs of other cancer types. Particularly, this lead to improved efficacy in treatment and even prevention of carcinogenesis of all types of cancers (Chang A; Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer 71:3-10, 2011.)
It was reported by Nguewa P A et al. that in advanced NSCLC (lung adenocarcinoma) patients with specific EGFR mutations, the treatment outcome of EGFR-TKIs was significantly better than traditional chemotherapy drugs (Nguewa P A et al.; Tyrosine kinase inhibitors with antiangiogenic properties for the treatment of non-small cell lung cancer. Expert Opin Investig Drugs 20:61-74, 2011; and Pao W and Chmielecki J; Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 10:760-74, 2010.) However, almost all patients who received EGFR-TKI treatment would eventually develop drug resistance. For instance, the median progression free survival after first-line treatment of gefitinib in sensitive EGFR mutated patients is about 10 months, and only 2.2 months in patients with erlotinib as second line treatment after chemotherapy. The exact mechanism(s) responsible for the development of drug resistance remains unclear, but the existence of CSCs presents a strong argument. There is currently no effective treatment to overcome drug resistance once it has emerged.